AXIN2 in hypoxic white matter damage in newborns & in MS

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Cece
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AXIN2 in hypoxic white matter damage in newborns & in MS

Post by Cece »

Credit to Cheer over on the CCSVI in MS facebook site for this:
http://www.nature.com/neuro/journal/vao ... .2855.html

It's a potential target for remyelination. Also noted is the similarity between white matter damage in newborns, which is caused by lack of oxygen due to poor lung development causing a disruption in the the creation of white matter, and white matter damage in MS. If hypoxia is the cause for the one, is hypoxia the cause for the other.
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cheerleader
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Post by cheerleader »

You are fast, Cece :D
Was just going to post. Found this new research VERY interesting.
We found that AXIN2 was expressed in immature oligodendrocyte progenitor cells (OLPs) in white matter lesions of human newborns with neonatal hypoxic-ischemic and gliotic brain damage, as well as in active multiple sclerosis lesions in adults.

Axin2 is a target of Wnt transcriptional activation that negatively feeds back on the pathway, promoting β-catenin degradation. We found that Axin2 function was essential for normal kinetics of remyelination.
Hope this leads to more reseach on remyelination, but hope it also continues research into MS as a disease of hypoxic injury...
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
Cece
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Post by Cece »

I'd have waited if I'd known you were planning to post here. :)
But this is very interesting.

From another article on the same research (worth reading for the lengthy explanations of the research):
The researchers found that the chemical XAV939 stabilised levels of Axin2 in OPCs in the laboratory. Slices of mouse brain in the laboratory, which had been starved of oxygen or exposed to a demyelinating chemical, showed reduced levels of myelin. Treating these slices of brain with XAV939 reversed this effect.
http://smashyevent.com/new-clues-on-ms-nerve-damage/

and elsewhere:
{Nature Publishing via BioPortfolio} Premyelinating oligodendrocytes are vulnerable to hypoxic injuries, especially during the neonatal period. Here, Fancy et al. find that the Wnt scaffolding molecule Axin2 is crucial for normal remyelination after hypoxic injuries and demonstrate that pharmacological inhibition of tankyrase, which stabilizes Axin2 levels, can promote oligodendrocyte differentiation and recovery after hypoxic and demyelinating injuries.
http://tinyurl.com/6gpjbb9
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cheerleader
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Post by cheerleader »

Another thing to mention is that in all of the reporting about this exciting discovery on MS Society page, there is no mention made of the tie-in to hypoxic injury in premature babies. None.
link
This is research that was funded in part by MS Societies. It's big news because there is a target that can be addressed with a pharmaceutical solution. But what about looking at the cause of the hypoxic injury? In premies, it is recognized as diminished lung capacity.....

Scientific America discusses the tie-in to "The most vulnerable brains"...those of premature babies.
link
just found that ommission on the MS page curious--
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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daniel
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Post by daniel »

I just found this yesterday and was going to post it as well. It had me thinking that if it's found in MS patients as well, it may be more to do with epigenetics(wikipedia link) .. in which this AXIN2 gene becomes expressed once hypoxic injury occurs.... (just thoughts)
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Post by Cece »

O2 availability, therefore, may have a direct role in stem cell regulation through HIF‑1α modulation of Wnt/β‑catenin signalling. Activation of the Wnt/β-catenin pathway is characterized by 1) stabilization of cytoplasmic β-catenin after receptor engagement by Wnt ligands; 2) β-catenin nuclear translocation, 3) β-catenin interaction with lymphoid enhancer-binding factor-1/T-cell factor-1 (LEF/TCF) transcription factors; and 4) stimulation of target genes8,9.

To determine whether this pathway is modulated by O2 availability, we transiently transfected murine ES cells and P19 embryonal carcinoma (EC)
cells with a luciferase-based TOP-Flash (TCF optimal promoter) Wnt
reporter plasmid, and compared reporter activity under normoxic (21%
O2) and hypoxic (1.5% O2) conditions. Exposure to hypoxia significantly
enhanced reporter activity (2-fold) in both embryonic cell lines
(Fig. 1a; Supplementary Information, Fig. S1a, b). Hypoxic exposure
also increased levels of nuclear β-catenin, LEF-1 and TCF-1 proteins
(Fig. 1b). Analysis of hypoxic cells by quantitative real-time PCR (qRT–
PCR) showed increased expression (2–6-fold) of Wnt target genes, such
as Axin2
and Dkk‑4 (Dickkopf-4), and β-catenin activators, Lef‑1 and
Tcf‑1 (Fig. 1c). This is consistent with our previous data showing
increased Lef‑1 expression in hypoxic mouse ES cells10. HIF-1α protein
stabilization and upregulation of the HIF-1α target Pgk‑1 confirmed the
induction of a hypoxic response (Fig. 1b, c). Hypoxia exerted a similar effect in stimulated cells.
http://bms.ucsf.edu/sites/ucsf-bms.ixm. ... 032011.pdf

There is an increased expression of Axin2 when cells are hypoxic. Axin2 is found in MS lesions although not in NAWM (this was in the originally posted research). Therefore hypoxia is the cause of the increased expression of Axin2 in MS lesions, unless there is any other reason for the Axin2 to increase?

I am not overly familiar with genetics, not to mention epigenetics, so it is ok if we go slowly here. :)
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cheerleader
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Post by cheerleader »

Brilliant find on that paper, Cece.
And great point, Daniel.
All epigenics means is that our DNA can be changed by environmental factors. My Dad was an identical twin. (this is actually true.) He developed Parkinsons, white matter lesions, and dementia and passed last year--- but his brother didn't. Something in my Dad's environment changed his genes. Something his twin brother was not exposed to.

Something environmental happens to allow for this increased expression of Axin2 genes. From the earlier research we know that they do not show up in normal appearing white matter. They show up in MS lesions, in premie brains that have been injured by hypoxia and in embryonic hypoxic cells. If it looks like hypoxia....
cheer
Husband dx RRMS 3/07
dx dual jugular vein stenosis (CCSVI) 4/09
http://ccsviinms.blogspot.com
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